This Breast Cancer SPORE application is being submitted by the Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University Medical Center, and affiliated institutions. The proposal comprises clinical, translational, and basic science investigators with significant NCI support related to the focus of the application. The thematics targeted are a natural extension on the funded research of SPORE investigators and include: novel clinical trials with assessment of surrogate markers of response, the identification of markers of breast cancer risk in pre-neoplastic syndromes, and the discovery of proteins predictive of breast cancer invasiveness and therapeutic response using imaging mass spectrometry. Project 1 will determine the antitumor effect of OSI-774, an inhibitor of the HER (erbB) signaling network in patients with operable breast cancer and identify a molecular profile associated with evidence of response in situ. This will identify a population that can be the target of randomized trials with HER signaling inhibitors. Project 2 will determine if paclitaxel administration to patients with locally advanced breast cancer leads to tumor cell transit into mitosis, loss of proliferation, and apoptosis, and if these events predict for tumor response. Both of these Projects will use imaging mass spectrometry to discover novel protein profiles predictive of drug action in two non-overlapping patient populations. Project 3 will use imaging mass spectrometry in microdissected primary breast cancers to identify proteins that segregate DCIS from invasive cancer and tumor from non-tumor stroma. In a mouse model of breast cancer this Project will spatially profile anticancer drugs with mass spectrometric evidence of drug action on established and novel protein targets. Project 4 will determine if alterations in components of the TGF-beta and EGF receptor pathways are associated with enhanced breast cancer risk in the Nashville Breast Cohort, a large cohort of women with 14 years of follow-up and with available archival material. This Project will also address for the first time in African-Americans in this cohort, whether breast cancer risk is affected by breast hyperplasia. To support these translational projects, we propose six CORES: Administrative and Outreach, Tissue, Proteomics and Emerging Technologies, Antibody Production and Characterization, Biostatistics, and Biomedical Informatics. The proposed Developmental Research (Pilot) and Career Development Programs are tightly integrated with Institutional initiatives and mechanisms that identify local research strengths as well as the best translational researchers. For these two Programs and the Tissue Core, the SPORE has harnessed significant matching support from the VICC and VUMC. The combined efforts and product of the translational and pilot projects, the career development awards, and the core resources in this SPORE application will impact the prevention, diagnosis, and treatment of breast cancer.